Regulation of muscle protein synthesis and the effects of catabolic states

Abstract

Protein synthesis and degradation are dynamically regulated processes that act in concert to control the accretion or loss of muscle mass. The present article focuses on the mechanisms involved in the impairment of protein synthesis that are associated with skeletal muscle atrophy. The vast majority of mechanisms known to regulate protein synthesis involve modulation of the initiation phase of mRNA translation, which comprises a series of reactions that result in the binding of initiator methionyl-tRNAi and mRNA to the 40S ribosomal subunit. The function of the proteins involved in both events has been shown to be repressed under atrophic conditions such as sepsis, cachexia, chronic kidney disease, sarcopenia, and disuse atrophy. The basis for the inhibition of protein synthesis under such conditions is likely to be multifactorial and includes insulin/insulin-like growth factor 1 resistance, pro-inflammatory cytokine expression, malnutrition, corticosteroids, and/or physical inactivity. The present article provides an overview of the existing literature regarding mechanisms and signaling pathways involved in the regulation of mRNA translation as they apply to skeletal muscle wasting, as well as the efficacy of potential clinical interventions such as nutrition and exercise in the maintenance of skeletal muscle protein synthesis under atrophic conditions. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting.

Keywords: 3-phosphoinositol-dependent kinase 1; 4E-BP1; 5′-UTR; 5′-untranslated region; 70kDa ribosomal protein S6 kinase 1; AMP-activated protein kinase; AMPK; GCN2; GEF; GSK-3; HRI; ICU; IGF-1; IRES; Inflammation; Insulin resistance; LPS; Met-tRNA(i); Muscle atrophy; NF-κB; PDCD4; PDK1; PERK; PI3K; PKR; PKR-like endoplasmic reticulum-associated protein kinase; REDD; Rheb; TNF; TSC; double-stranded RNA-dependent protein kinase; eIF; eIF4E binding protein 1; eukaryotic initiation factor; general-control nonderepressible; glycogen synthase kinase-3; guanine nucleotide exchange factor; heme-regulated inhibitor; initiator methionyl-tRNA; insulin-like growth factor-1; intensive care unit; internal ribosome entry site; lipopolysaccharide; mRNA translation; mTOR; mTORC1; mechanistic target of rapamycin in complex 1; nuclear factor kappa-B; p70S6K1; phosphatidylinositol-4,5-bisphosphate 3-kinase; programmed cell death 4; ras homolog enriched in brain; regulated in DNA damage and development; tuberous sclerosis complex; tumor necrosis factor; uORF; upstream open reading frame.

Figure 1. Impairment of protein synthesis in various skeletal muscle wasting diseases is associated with inflammation, malnutrition, myostatin, and insulin resistance

Hormones such as insulin and insulin-like growth factor 1 (IGF-1) stimulate protein synthesis through both the Akt/mTORC1 signaling pathway and activation of eIF2B, while amino acids activate mTORC1 signaling through the Rag proteins. Cell signaling pathways are depicted by black lines (arrows represent stimulatory pathways; lines with blunt ends represent inhibitory). Skeletal muscle wasting diseases, including sarcopenia, cachexia, disuse, sepsis, and chronic kidney disease (CKD), impair signaling through these pathways at specific steps depicted by gray lines.